A Genetic Mouse Model of Parkinson’s Disease Shows Involuntary Movements and Increased Postsynaptic Sensitivity to Apomorphine

Abstract

Alpha-synuclein (SNCA) protein aggregation plays a causal role in Parkinson's disease (PD). The SNCA protein modulates neurotransmission via the SNAP receptor (SNARE) complex assembly and presynaptic vesicle trafficking. The striatal presynaptic dopamine deficit is alleviated by treatment with levodopa (L-DOPA), but postsynaptic plastic changes induced by this treatment lead to a development of involuntary movements (dyskinesia). While this process is currently modeled in rodents harboring neurotoxin-induced lesions of the nigrostriatal pathway, we have here explored the postsynaptic supersensitivity of dopamine receptor-mediated signaling in a genetic mouse model of early PD. To this end, we used mice with prion promoter-driven overexpression of A53T-SNCA in the nigrostriatal and corticostriatal projections. At a symptomatic age (18 months), mice were challenged with apomorphine (5 mg/kg s.c.) and examined using both behavioral and molecular assays. After the administration of apomorphine, A53T-transgenic mice showed more severe stereotypic and dystonic movements in comparison with wild-type controls. Molecular markers of extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and dephosphorylation, and Fos messenger RNA (mRNA), were examined in striatal tissue at 30 and 100 min after apomorphine injection. At 30 min, wild-type and transgenic mice showed a similar induction of phosphorylated ERK1/2, Dusp1, and Dusp6 mRNA (two MAPK phosphatases). At the same time point, Fos mRNA was induced more strongly in mutant mice than in wild-type controls. At 100 min after apomorphine treatment, the induction of both Fos, Dusp1, and Dusp6 mRNA was significantly larger in mutant mice than wild-type controls. At this time point, apomorphine caused a reduction in phospho-ERK1/2 levels specifically in the transgenic mice. Our results document for the first time a disturbance of ERK1/2 signaling regulation associated with apomorphine-induced involuntary movements in a genetic mouse model of synucleinopathy. This mouse model will be useful to identify novel therapeutic targets that can counteract abnormal dopamine-dependent striatal plasticity during both prodromal and manifest stages of PD.

Potentiation of neurotoxicity in double-mutant mice with Pink1 ablation and A53T-SNCA overexpression

“…A known phenotype of decreased Lect1 levels is elevated levels of H2AX phosphorylation ( 50 ). Further GSEA findings included significant upregulations in the NAGASHIMA_EGF_SIGNALING_UP signature for cerebellum at both ages ( Supplementary Material, Figs S7 and S8 ), which were similarly observed for Dusp1/Dusp6 and c-Fos already in the SM PrPmtA line in striatum of 18-month-old mice ( 51 ).…”

Blood RNA biomarkers in prodromal PARK4 and REM sleep behavior disorder show role of complexin-1 loss for risk of Parkinson's disease

“…In an initial candidate gene study, we studied the blood expression of all PARK genes, of the previously reported PD blood biomarker ST13 and of promising transcripts that encode putative SNCA-interactor proteins (Fig. 2A,B) and showed altered levels in our previous global transcriptome profiling of midbrain tissue in a carefully characterized synucleinopathy mouse model with dopaminergic deficits, impaired synaptic plasticity and mitochondrial dysfunction (Kurz et al, 2010; Platt et al, 2012; Tozzi et al, 2012; Gispert et al, 2015a,b; Subramaniam et al, 2014; Brehm et al, 2015b). SNCA gene duplication in the Turkish pedigree showed no correlation with the expression of other genes with known association with PD risk or of the previously reported PD blood biomarker ST13 (Scherzer et al, 2007).…”

Parkinson’s disease: animal models and dopaminergic cell vulnerability

“…However, recently viral vector-mediated silencing of TH was used to induce striatal DA depletion without affecting the anatomical integrity of the presynaptic terminals and study LID ( Ulusoy et al, 2010 ). And more recently, for the first time, a genetic mouse model overexpressing A53T α-syn in nigrostriatal and corticostriatal projection neurons shows involuntary movements and increased post-synaptic sensitivity to apomorphine ( Brehm et al, 2014 ). It seems unlikely that a single model can fully recapitulate the complexity of the human disease.…”